Project Summary/Abstract Viruses can establish persistent infections by escaping or suppressing the host immune system. The clone 13 strain (Cl 13) of lymphocytic choriomeningitis virus (LCMV) induces a profound immune suppression and persists in the mouse, its natural host. The immunosuppression caused by LCMV Cl 13 infection is principally due to the impairment of anti-viral T cell responses, which is also observed during chronic viral infections in humans. Therefore, LCMV infection of mice is a valuable animal model for studying the interplay between the virus and the host immune system. Sphingosine kinase (SK) 2 mediates the generation of sphingosine 1- phosphate from sphingosine and regulates multiple cellular conditions including host immunity. However, the role of SK2 in host immune responses to virus infection has not been explored. Preliminary data demonstrate that SK2 deficiency results in heightened T cell responses to LCMV Cl 13 infection, leading to lethal immunopathology. The data also indicate that LCMV Cl 13 increases the expression and activation of SK2 in CD4 T cells, which inhibits the expansion of virus-specific T cells. Therefore, in this proposal, the role of SK2 in the suppression of virus-specific, functional T cell responses will be determined during persistent LCMV infection. The intrinsic function of SK2 in virus-specific CD4 T cells will be investigated by using LCMV-specific TCR transgenic T cells. Also, the molecular mechanisms by which SK2 causes CD4 T cell suppression upon infection will be studied. Additionally, we will investigate if T cell-extrinsic functions of SK2 in non-hematopoietic cells and programming of innate cytokine profiles affect virus-induced T cell suppression. Collectively, this research is expected to produce new information about the SK2-mediated T cell suppressive pathway upon viral infection. The proposed project could act as foundation to develop immune therapeutics for the treatment of chronic viral infections.